Epilepsy is a devastating condition with no cure as yet, and many patients suffer from seizures that are resistant to current treatment options. Many changes in the brain occur during epileptogenesis, but it has been difficult to distinguish those that are directly pathological from those that are merely compensatory. This complexity presents a major obstacle in identifying novel therapeutic targets. One potential target is the GABAA receptor subunit, which mediates tonic inhibition in many brain regions. The expression of this subunit decreases in principal neurons in the hippocampus during epileptogenesis, but the interpretation of this change is uncertain because it is not understood why the brain utilizes two forms of inhibition, tonic and phasic. This project utilizes a novel conditional-knockout mouse line to selectively examine the function of tonic versus phasic inhibition. By dissociating the two types of inhibition, we will uncover the role of tonic inhibition in normal hippocampal function as well as under pathological conditions, such as epileptogenesis. This proposal employs a multifaceted approach, from the examining the role of tonic inhibition in individual neurons to an entire network of neurons, to animal behavior and in vivo models of epileptogenesis. The results will provide information as to the role of tonic inhibition in the CNS as well as to evaluate the potential of these receptors in the development of new treatments for epilepsy.